ATP-sensitive potassium (KATP) channels of islet -cells play a key role in glucose-stimulated insulin secretion by coupling glucose metabolism to membrane excitability. The -cell KATP channel is formed by the sulfonylurea receptor SUR1 and the inward rectifier potassium channel Kir6.2. Loss-of-function mutations in SUR1 and Kir6.2 are the primary cause of congenital hyperinsulinism. In contrast, gain-of-function channel mutations cause the opposite disease neonatal diabetes. The long-term goal of our research is to understand regulation of -cell KATP channels, how this regulation is perturbed in disease and how we may manipulate channel regulation to combat insulin secretion disorders. Work supported by this grant to date has established the importance of channel biogenesis and trafficking in the context of disease. In this renewal application, we propose to study how KATP channel density in the -cell membrane is regulated by physiological signals to control insulin secretion. This is based on our preliminary finding that leptin, which is known to inhibit insulin secretion as part of the adipoinsular axis feedback regulation, markedly increases surface expression of KATP channels in -cells. A major goal of this application is to test the hypothesis that leptin promotes KATP channel trafficking to the cell surface by triggering a signaling cascade to increase KATP conductance and inhibit insulin secretion. In addition, we propose to continue our efforts on developing pharmacological agents that can overcome the trafficking defects of mutant KATP channels as a novel therapeutic strategy for congenital hyperinsulinism. To this end, we have obtained preliminary results on several promising small molecules that enhance channel surface expression. Thus, a second major goal of this application is to test the hypothesis that surface expression and function of trafficking-impaired KATP mutants identified in congenital hyperinsulinism can be restored by small molecule chaperones to recover -cell function. We will combine biochemical, imaging and electrophysiology approaches to test the above hypotheses. In Aim 1, we will elucidate the signaling and cellular mechanisms by which leptin increases surface expression of -cell KATP channels. In Aim 2, we will identify and characterize novel pharmacological chaperones that rescue trafficking-impaired KATP channels in COS cells and rodent and human islets/-cells. The research is innovative because it tests novel concepts in physiological and pharmacological regulation of KATP channel trafficking in -cells using unique tools and knowledge developed by our lab for these channels. The research is significant from both human health and basic science standpoints. It will identify new chemical compounds that can correct channel trafficking defects caused by disease mutations, thus giving it high translational potential. Moreover, it will reveal novel physiological signaling mechanisms that may be exploited to control KATP channel surface expression, thereby glucose-secretion coupling in patients with insulin secretion disease. PUBLIC HEALTH RELEVANCE: ATP-sensitive potassium (KATP) channels play a key role in regulating insulin secretion and dysfunction of KATP channels causes abnormal insulin secretion in human as seen in diabetes and hyperinsulinism. The goal of this project is to understand how the abundance of channels in the pancreatic -cell membrane is regulated by physiological signals such as leptin and glucose and by pharmacological agents to affect insulin secretion. The research will lead to development of novel therapeutic strategies for diseases caused by channel misregulation.